U.S. patent number 6,730,796 [Application Number 10/399,096] was granted by the patent office on 2004-05-04 for process for preparation of n-substituted 2-sulfanylimidazoles.
This patent grant is currently assigned to Chugai Seiyaku Kabushiki Kaisha. Invention is credited to Mi Chen, Jie Fei Cheng.
United States Patent |
6,730,796 |
Cheng , et al. |
May 4, 2004 |
Process for preparation of N-substituted 2-sulfanylimidazoles
Abstract
This invention provides a process for preparing an N-substituted
2-sulfanylimidazole compound of the formula (I) ##STR1## by
reacting an isothiocyanate of the formula R.sub.1 NCS with an
.alpha.-aminocarbonyl compound of the formula NH.sub.2 CHR.sub.4
C(OP).sub.2 R.sub.3 and an alkyl halide or an activated aryl halide
of the formula R.sub.2 X in a solvent, alternatively, by reacting
an isothiocyanate of the formula R.sub.1 NCS with an
.alpha.-aminocarbonyl compound of the formula NH.sub.2 CHR.sub.4
C(OP).sub.2 R.sub.3 before adding an alkyl halide of the formula
R.sub.2 X, wherein R.sub.1 and R.sub.2 independently represent
alkyl, heterocyclyl, aryl, or heteroaryl groups; R.sub.3 and
R.sub.4 independently represent hydrogen, alkyl, heterocyclyl, aryl
or heteroaryl or may form a non-aromatic ring; P represents a
protecting group of a carbonyl group.
Inventors: |
Cheng; Jie Fei (Carlsbad,
CA), Chen; Mi (San Diego, CA) |
Assignee: |
Chugai Seiyaku Kabushiki Kaisha
(Tokyo, JP)
|
Family
ID: |
22910998 |
Appl.
No.: |
10/399,096 |
Filed: |
April 14, 2003 |
PCT
Filed: |
October 12, 2001 |
PCT No.: |
PCT/US01/42672 |
PCT
Pub. No.: |
WO02/32877 |
PCT
Pub. Date: |
April 25, 2002 |
Current U.S.
Class: |
548/325.1 |
Current CPC
Class: |
C07D
233/84 (20130101); C07D 235/28 (20130101); Y02P
20/55 (20151101) |
Current International
Class: |
C07D
233/84 (20060101); C07D 233/00 (20060101); C07D
233/84 () |
Field of
Search: |
;548/325.1 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Elslager, E. F., et al., J. Heterocyclic Chem., Jan. 1980, pp.
129-136, vol. 17. .
Hofmann, K., "The Chemistry of Heterocyclic Compounds", ed. by A.
Weissberger, 1953, pp. 86-87, Interscience Publishers Inc., New
York. .
Uno, T., et al., Chem. Pharm. Bull., Oct. 1995, pp. 1724-1733, vol.
43, No. 10. .
Yamada, M., et al., J. Med. Chem., 1996, pp. 596-604, vol. 39, No.
2..
|
Primary Examiner: Stockton; Laura L.
Attorney, Agent or Firm: Collins; Daniel W.
Parent Case Text
This application claims the benefit of Provisional application Ser.
No. 60/241,516 filed Oct. 16, 2000.
Claims
We claim:
1. A process for preparing an N-substituted 2-sulfanylimidazole
compound of the formula ##STR4##
by reacting an isothiocyanate of the formula R.sub.1 NCS with an
.alpha.-aminocarbonyl compound of the formula NH.sub.2 CHR.sub.4
C(OP).sub.2 R.sub.3 and an alkyl halide or an activated aryl halide
of the formula R.sub.2 X in a solvent, wherein R.sub.1 and R.sub.2
independently represent alkyl, heterocyclyl, aryl, or heteroaryl
groups; R.sub.3 and R.sub.4 independently represent hydrogen,
alkyl, heterocyclyl, aryl or heteroaryl or may form a non-aromatic
ring; P represents a protecting group of a carbonyl group and
wherein X is a halide.
2. The process of claim 1, wherein R.sub.1 represents aryl or
heteroaryl.
3. The process of claim 1, wherein R.sub.2 represents alkyl.
4. The process of claim 1, wherein R.sub.3 represents hydrogen.
5. The process of claim 1, wherein R.sub.4 represents hydrogen.
6. The process of claim 1, wherein said halide is added after
mixing said isocyanate and said .alpha.-aminocarbonyl compound.
7. The process of claim 1, wherein the reaction is conducted under
a sealed condition.
8. The process of claim 1, wherein the reaction is conducted in a
large scale.
9. The process of claim 1, wherein the reaction is conducted at a
elevated temperature.
Description
FIELD OF INVENTION
This invention relates to a novel process for preparing
N-substituted 2-sulfinylimidazoles compounds.
BACKGROUND
2-Sulfanylimidazoles are important heterocycles that are used in a
number of pharmaceutical drugs or drug candidates. For example,
both a GPIIB-IIIA antagonist OPC-29030 (Chem. Pharm. Bull. 43(10),
1724 (1995); CAS RNS: 161190-39-2) and an antiulcer agent T-330
(CSA RNS: 52410-51-2) which are in clinical trials contain an
N-aryl 2-sulfanylimidazole substructure. On the other hand, a
series of 4,5-unsubstituted 2-sulfanylimidazoles are described as
potent inhibitors of the acid secretory enzyme H.sup.+ /K.sup.+
-ATPase (Yamada, M. et al.; J. Med. Chem. 39, 596 (1996)). These
2-sulfanylimidazoles are generally prepared from
imidazole-2-thiones or imidazoles through alkylation with alkyl
halides or activated aryl halides in the presence of bases. Either
approach requires stepwise preparation and isolation of the
respective intermediates. Furthermore, imidazole-2-thiones are
typically synthesized from a thiourea acetal intermediate via an
acid-catalyzed cyclization (Hofmann, K. in "The Chemistry of
Heterocyclic Compounds", eds. By A. Weissberger, Interscience
Publishers Inc., New York, 1953, p86-87; Elslager, E. F. et al., J.
Heterocyclic Chem. 17, 129 (1980)). The reactions mentioned above
were conducted under either strongly acidic or basic conditions
which are incompatible with many functional groups.
SUMMARY OF THE INVENTION
The inventors have developed a convenient one step synthesis of
N-substituted 2-sulfanylimidazole compounds without using a base or
an acid, thus allowing for functional groups that would otherwise
be incompatible with such a reaction.
This invention relates to a process for preparing an N-substituted
2-sulfanylimidazole compound of the formula (I) ##STR2##
by reacting an isothiocyanate of the formula R.sub.1 NCS with an
.alpha.-aminocarbonyl compound of the formula NH.sub.2 CHR.sub.4
C(OP).sub.2 R.sub.3 and an alkyl halide or an activated aryl halide
of the formula R.sub.2 X in a solvent, alternatively, by reacting
an isothiocyanate of the formula R.sub.1 NCS with an
.alpha.-aminocarbonyl compound of the formula NH.sub.2 CHR.sub.4
C(OP).sub.2 R.sub.3 before adding an alkyl halide or an activated
aryl halide of the formula R.sub.2 X, wherein R.sub.1 and R.sub.2
independently represent alkyl, heterocyclyl, aryl, or heteroaryl
groups; R.sub.3 and R.sub.4 independently represent hydrogen,
alkyl, heterocyclyl, aryl or heteroaryl or may form a non-aromatic
ring; P represents a protecting group of a carbonyl group.
Preferably, R.sub.1 represents aryl or heteroaryl. Preferably,
R.sub.2 represents alkyl. Preferably, R.sub.3 represents hydrogen.
Preferably, R.sub.4 represents hydrogen. Preferably, said halide is
chloride, bromide or iodide. Preferably, the protecting group of
the carbonyl group of .alpha.-aminocarbonyl is dialkyl or cyclic
alkyl acetal.
This invention relates to a convenient one step synthesis of
N-substituted 2-sulfanylimidazole from an isothiocyanate, an
.alpha.-aminocarbonyl compound and an alkyl halide or an activated
aryl halide. Reaction of an isothiocyanate with an
.alpha.-aminocarbonyl compound affords a thiourea acetal
intermediate, which without isolation or purification provides the
desired N-substituted 2-sulfanylimidazole upon treatment with an
alkyl halide.
DETAILED DESCRIPTION OF THE INVENTION
The detailed description of the invention which follows is not
intended to be exhaustive or to limit the invention to the precise
details or examples disclosed. Details and examples have been
chosen to explain the invention to others skilled in the art.
The processes of this invention described herein and in the claims,
may be performed in s veral ways. Preferred methodologies are
described as follows.
This invention provides a process for preparing an N-substituted
2-sulfanylimidazole compound of the formula (I) ##STR3##
by reacting an isothiocyanate of the formula R.sub.1 NCS with an
.alpha.-aminocarbonyl compound of the formula NH.sub.2 CHR.sub.4
C(OP).sub.2 R.sub.3 and an alkyl halide or an activated aryl halide
of the formula R.sub.2 X in a solvent, alternatively, by reacting
an isothiocyanate of the formula R.sub.1 NCS with an
.alpha.-aminocarbonyl compound of the formula NH.sub.2 CHR.sub.4
C(OP).sub.2 R.sub.3 before adding an alkyl halide of the formula
R.sub.2 X, wherein R.sub.1 and R.sub.2 independently represent
alkyl, heterocyclyl, aryl, or heteroaryl groups; R.sub.3 and
R.sub.4 independently represent hydrogen, alkyl, heterocyclyl, aryl
or heteroaryl or may form a non-aromatic ring; P represents a
protecting group of a carbonyl group.
Preferably, R.sub.1 represents aryl or heteroaryl. Preferably,
R.sub.2 represents alkyl. Preferably, R.sub.3 represents hydrogen.
Preferably, R.sub.4 represents hydrogen. Preferably, said halide is
chloride, bromide or iodide. Preferably, the protecting group of
the carbonyl group of .alpha.-aminocarbonyl is dialkyl or cyclic
alkyl acetal.
The reaction is performed by mixing all reactants, i.e., an
isothiocyanate of the formula R.sub.1 NCS, an .alpha.-aminocarbonyl
compound of the formula NH.sub.2 CHR.sub.4 C(OP).sub.2 R.sub.3 and
an alkyl halide of the formula R.sub.2 X in a solvent.
Alternatively, an isothiocyanate of the formula R.sub.1 NCS is
reacted with a protected .alpha.-aminocarbonyl compound of the
formula NH.sub.2 CHR.sub.4 C(OP).sub.2 R.sub.3 in a solvent to
provide a thiourea intermediate. There is no restriction on the
solvent used in this reaction. The reaction can be conducted in
either organic or inorganic solvents. Preferably, the solvents used
in the invention are organic solvents. More preferably, the
reaction is conducted in an organic solvent, such as toluene or
ethanol. Subsequently, the thiourea intermediate is reacted with an
alkyl halide to provide the desired N-substituted
2-sulfanylimidazole compound. Preferably, the reaction is conducted
under sealed condition. Preferably, alcohol solvent is added along
with an alkyl halide or an activated aryl halide. Preferably, the
reaction is conducted at elevated temperature aftermixing all
reactants. More preferably, the reaction is heated to 60-80.degree.
C. from room temperature. The reaction is useful for a large scale
production of N-substituted 2-sulfanylimidazoles. This invention is
useful for preparing important pharmaceutical agents such as drugs
or drug candidates which contain N-substituted
2-sulfanylimidazoles.
DEFINITION
As used above, and throughout the description of the invention, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings:
"Activated aryl halide", as used herein, means an aryl halide that
is substituted by some type of substituents that activate the aryl
halide so that it can be reacted with thiourea intermediate to form
the desired N-substituted 2-sulfanylimidazole. Substituents used
for activation of an aryl halide are electron-withdrawing
groups.
"Alkyl", as used herein, means a cyclic, branched, or straight
chain chemical group containing only carbon and hydrogen, such as
methyl, pentyl, and adamantyl. Alkyl groups can either be
unsubstituted or substituted with one or more substituents, e.g.,
halogen, alkoxy, acyloxy, amino, cyano, nitro, hydroxyl, mercapto,
carboxy, benzyloxy, aryl, heteroaryl, or other functionality that
may be suitably blocked, if necessary for purposes of the
invention, with a protecting group. Alkyl groups can be saturated
or unsaturated (e.g., containing --C.dbd.C-- or --C.dbd.C--
subunits), at one or several positions. Typically, alkyl groups
will comprise 1 to 12 carbon atoms, preferably 1 to 10, and more
preferably 1 to 8 carbon atoms.
"Aryl", as used herein, means a monovalent unsaturated aromatic
carbocyclic group having a single-ring (e.g., phenyl) or multiple
condensed rings (e.g., naphthyl or anthryl), which can be
optionally unsubstituted or substituted with amino, cyano,
hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto,
and other substituents.
"Electron-withdrawing group", as used herein, means a specific
group that makes the electron density of the parent molecule
unevenly distributed when it is attached to the parent molecule. An
electron-withdrawing group pulls the electron from the parent
molecule toward this group. An electron-withdrawing group includes
but not limited to a nitro, cyano or trifluoromethyl group. More
examples of electron-withdrawing groups can be found in March,
Advanced Organic Chemistry, 4.sup.th, Wiley Interscience, 1992.
"Elevated temperature", as used herein, means the reaction is
conducted at a temperature that is higher than room temperature.
The reaction in the invention is conducted at a temperature ranging
from 60 to 80.degree. C. after all the reactants are added.
"Halo", as used herein, means chloro, bromo or iodo atoms in the
invention. The fluorine atom is excluded in the invention. A
compound containing halo atom is referred as a halide.
"Heteroaryl", as used herein, means a monovalent unsaturated
aromatic carbocyclic group having a single ring (e.g., pyrridyl or
furyl) or multiple condensed rings (e.g., indolizinyl or
benzothienyl) and having at least one hetero atom, such as N, O, or
S, within the ring, which can optionally be unsubstituted or
substituted with amino, cyano, nitro, hydroxyl, alkyl, haloalkyl,
alkoxy, aryl, halo, mercapto, and other substituents.
"Heterocyclyl", as used herein, means radical heterocycles which
are saturated, or unsaturated and non-aromatic. These may be
substituted or unsubstituted, and are attached to the core
structure via any available valence, preferably any available
carbon. More preferred heterocycles are of 5 or 6 members. In six
membered non-aromatic monocyclic heterocycles, the heteroatom(s)
are from one to three Ns, and wherein when the heterocycle is five
membered and non-aromatic, preferably it has one or two heteroatoms
selected from O, N, or S.
"Large scale", as used herein, means that the reaction provides the
desired product in an industrial scale or in a large quantity. The
reaction in the invention can be used either to produce a picogram,
milligram, or gram quantity or to produce on the kilogram or tons
scale.
"Protecting group", as used herein, means a chemical group that
exhibits the following characteristics: 1) reacts selectively with
the desired functionality in good yield to give a protected
substrate that is stable to the projected reactions for which
protection is desired; 2) is selectively removable from the
protected substrate to yield the desired functionality; and 3) is
removable in good yield by reagents compatible with the other
functional group(s) generated in such protected reactions. Most
wildly used protecting group for a carbonyl functionality is acetal
(or ketal). Examples of more protecting groups can be found in
Greene and Wuts, Protective Groups in Organic Synthesis, 2.sup.nd
Ed. John Wiley & Sons, (1991).
"Sealed condition", as herein used, means that the reaction is
conducted in a container that is not exposed to air directly. Any
isolated system that is not exposed directly to air is a sealed
system. For example, the reactions performed in a sealed tube or in
a capped container or under argon or other inert gas atmosphere are
considered to be under sealed condition.
"Solvent", as herein used, means a liquid that can dissolve another
compound and has no adverse effect on the reaction or on the
reagents involved. Examples of suitable solvents include alcohols
(methanol, 1-butanol, phenol, trifluoroethanol,
hexafluoro-2-propanol, etc.), hydrocarbons (benzene, toluene,
etc.), amides (dimethyl acetamide, dimethylformamide, etc.),
halides (dichloroethane, dichloroiethane, etc.), and ethers
(tetrahydrofuran, dioxane, etc.). Other solvents include water,
1-methyl-2-pyrrolidine, diethyl phosphite, tetramethaylsulphone,
dimethyl sulphoxide, acetonitrile and pyridine.
The following abbreviations have the indicated meanings: Bn=benzyl
CDCl.sub.3 =deutered chloroform CH.sub.2 Cl.sub.2 =dichloromethane
ESIMS=electron spray mass spectrometry EtOAc=ethyl acetate
EtOH=ethanol Ph=phenyl TLC=thin layer chromatography Me=methyl
Et=ethyl n-Bu=normal butyl t-Bu=tertiary butyl
EXAMPLES
To further illustrate this invention, the following examples are
included. The examples should not, of course, be construed as
specifically limiting the invention. Variations of these examples
within the scope of the claims are within the purview of one
skilled in the art are considered to fall within the scope of the
invention as described, and claimed herein. The reader will
recognize that the skilled artisan, armed with the present
disclosure, and skill in the art is able to prepare and use the
invention without exhaustive examples.
Trademarks used herein are examples only and reflect illustrative
materials used at the time of the invention. The skilled artisan
will recognize that variations in lot, manufacturing processes, and
the like, are expected. Hence the examples, and the trademarks used
in them are non-limiting, and they are not intended to be limiting,
but are merely an illustration of how a skilled artisan may choose
to perform one or more of the embodiments of the invention.
.sup.1 H nuclear magnetic resonance spectra (NMR) is measured in
CDCl.sub.3 or other solvents as indicated by a Varian NMR
spectrometer (Unity Plus 400, 400 MHz for .sup.1 H) unless
otherwise indicated and peak positions are expressed in parts per
million (ppm) downfield from tetramethylsilane. The peak shapes are
denoted as follows, s, singlet; d, doublet; t, triplet; m,
multiplet.
Example 1
General Procedure for the Synthesis of N-substituted
2-Sulfanylimidazoles (1)
Isothiocyanate (1 mmol) and .alpha.-aminocarbonyl compound (1 mmol)
were mixed together in toluene or ethanol (2 mL). The reaction
mixture was allowed to stir at room temperature under argon until
the reaction is completed as evidenced by TLC. After addition of a
halide (1.5 mmol) in EtOH (2 mL), the reaction mixture was heated
to 80.degree. C. for 14 hrs under sealed condition. The solvent was
removed under reduced pressure and the resulting residue was
purified by a preparative TLC with 5% acetone in CH.sub.2 Cl.sub.2
to afford the desired N-substituted 2-sulfanylimidazole.
Example 2
General Procedure for the Synthesis of N-substituted
2-Sulfanylimidazoles (2)
Isothiocyanate (1 mmol), .alpha.-aminocarbonyl compound (1 mmol)
and a halide (1.5 mmol) in EtOH (2 mL) are mixed together in
toluene or ethanol (2 mL) at the room temperature under argon
atmosphere. The reaction mixture is heated to 80.degree. C. for 14
hrs under sealed condition. The solvent is removed under reduced
pressure and the resulting residue is purified by a preparative TLC
with 5% acetone in CH.sub.2 Cl.sub.2 to afford the desired
N-substituted 2-sulfanylimidazole.
Example 3
Preparation of Give N-(p-methoxyphenyl)-2-benzylthioimidazole
p-Methoxyphenylisocyanate (1 mmol) and aminoacetaldehyde diethyl
acetal (1 mmol) were mixed together in toluene (2 mL). The reaction
mixture was allowed to stir at room temperature under argon until
the reaction is completed as evidenced by TLC. After addition of
benzyl bromide (1.5 mmol) in EtOH (2 mL), the reaction mixture was
heated to 80.degree. C. for 14 hrs. Following removal of the
solvent, the residue was purified by preparative TLC with 5%
acetone in dichloromethane to give
N-(p-methoxyphenyl)-2-benzylthioimidazole in 92.1% yield. .sup.1 H
NMR (CDCl.sub.3) .delta.7.2 (brs, 6H), 7.0 (m, 3H), 6.8 2 (m, 2H),
4.21 (s, 2H), 3.78 (s, 3H). ESIMS: m/z 297 (M+H), C.sub.17 H.sub.16
N.sub.2 OS.
Example 4
The following compounds are also exemplified in this invention.
No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 1 Ph p-tBu-Bn H H 2 Ph m-MeOBn
H H 3 p-MeOPh Bn H H 4 Ph Allyl H H 5 Ph p-NO.sub.2 Bn H H 6 Ph
Cyclohexylmethyl H H 7 Ph o-Methylpropyl H H 8 Ph Me H p-MeOPh 9 Ph
Me Me H 10 p-CF.sub.3 Ph Bn --CH.sub.2 CH.sub.2 CH.sub.2 --
* * * * *